Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells

Jean Philippe Gratton, Manuel Morales-Ruiz, Yasuko Kureishi, David J Fulton, Kenneth Walsh, William C. Sessa

Research output: Contribution to journalArticle

242 Citations (Scopus)

Abstract

Vascular endothelial growth factor (VEGF) utilizes a phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling pathway to protect endothelial cells from apoptotic death. Here we show that PI 3-kinase/Akt signaling promotes endothelial cell survival by inhibiting p38 mitogen-activated protein kinase (MAPK)-dependent apoptosis. Blockade of the PI 3-kinase or Akt pathways in conjunction with serum withdrawal stimulates p38-dependent apoptosis. Blockade of PI 3-kinase/Akt also led to enhanced VEGF activation of p38 and apoptosis. In this context, the pro-apoptotic effect of VEGF is attenuated by the p38 MAPK inhibitor SB203580. VEGF stimulation of endothelial cells or infection with an adenovirus expressing constitutively active Akt causes MEKK3 phosphorylation, which is associated with decreased MEKK3 kinase activity and down-regulation of MKK3/6 and p38 MAPK activation. Conversely, activation-deficient Akt decreases VEGF-stimulated MEKK3 phosphorylation and increases MKK/p38 activation. Activation of MKK3/6 is not dependent on Rac activation since dominant negative Rac does not decrease p38 activation triggered by inhibition of PI 3-kinase. Thus, cross-talk between the Akt and p38 MAPK pathways may regulate the level of cytoprotection versus apoptosis and is a new mechanism to explain the cytoprotective actions of Akt.

Original languageEnglish (US)
Pages (from-to)30359-30365
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number32
DOIs
StatePublished - Aug 10 2001
Externally publishedYes

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1-Phosphatidylinositol 4-Kinase
Cytoprotection
Endothelial cells
Vascular Endothelial Growth Factor A
p38 Mitogen-Activated Protein Kinases
Down-Regulation
Endothelial Cells
Chemical activation
Phosphatidylinositols
Phosphotransferases
Apoptosis
Phosphorylation
Adenoviridae Infections
Protein Kinase Inhibitors
Cell Survival
Cell Death
Serum

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells. / Gratton, Jean Philippe; Morales-Ruiz, Manuel; Kureishi, Yasuko; Fulton, David J; Walsh, Kenneth; Sessa, William C.

In: Journal of Biological Chemistry, Vol. 276, No. 32, 10.08.2001, p. 30359-30365.

Research output: Contribution to journalArticle

Gratton, Jean Philippe ; Morales-Ruiz, Manuel ; Kureishi, Yasuko ; Fulton, David J ; Walsh, Kenneth ; Sessa, William C. / Akt Down-regulation of p38 Signaling Provides a Novel Mechanism of Vascular Endothelial Growth Factor-mediated Cytoprotection in Endothelial Cells. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 32. pp. 30359-30365.
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